Primary hyperparathyroidism is a relatively common endocrine disorder that is no longer characterized by classic symptomatic features seen in the past. Previously held concepts about the disease are being carefully re-evaluated in light of its current, often asymptomatic profile. The overall objective of this research program, now in its 13th year, is to definitively establish the extent, course and reversibility of primary hyperparathyroidism. In the renewal period, the following Specific Aims will be pursued: 1) to define the natural history of primary hyperparathyroidism and the reversibility of its manifestations over a uniquely long, systematic 18-year period of inquiry; 2) to evaluate cardiovascular and cognitive features of the disease; 3) to identify subgroups of patients with the disease who may be at risk for deleterious outcomes and thereby to establish new criteria for surgical or medical management; 4) to characterize biochemical mediators of parathyroid hormone action as they relate to indices of disease activity, to pathophysiological consequences, and to postoperative recovery; and 5) to reconstruct the bone remodeling unit in primary hyperparathyroidism by comprehensive two- and three-dimensional histomorphometric analysis of bone, before and after surgery. It is suggested by the applicant that, by the end of the renewal period, close to one hundred patients will have been followed prospectively, with or without parathyroid surgery, for an average of 12-13 years, making this the longest and most definitive study of its kind ever successfully conducted.